Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification of the gene responsible for gelatinous drop-like corneal dystrophy

Nature Genetics volume 21, pages 420–423 (1999)Cite this article

Abstract

Gelatinous drop-like corneal dystrophy (GDLD; OMIM 204870) is an autosomal recessive disorder characterized by severe corneal amyloidosis leading to blindness1,2,3,4, with an incidence of 1 in 300,000 in Japan5. Our previous genetic linkage study localized the gene responsible to a 2.6-cM interval on chromosome 1p (ref. 6). Clinical manifestations, which appear in the first decade of life, include blurred vision, photophobia and foreign-body sensation. By the third decade, raised, yellowish-grey, gelatinous masses severely impair visual acuity, and lamellar keratoplasty is required for most patients5. Here we report DNA sequencing, cDNA cloning and mutational analyses of four deleterious mutations (Q118X, 632delA, Q207X and S170X) in M1S1 (formerly TROP2 and GA733-1), encoding a gastrointestinal tumour-associated antigen. The Q118X mutation was the most common alteration in the GDLD patients examined, accounting for 33 of 40 (82.5%) disease alleles in our panel of families. Protein expression anaysis revealed aggregation of the mutated, truncated protein in the perinuclear region, whereas the normal protein was distributed diffusely in the cytoplasm with a homogenous or fine granular pattern. Our successful identification of the gene that is defective in GDLD should facilitate genetic diagnosis and potentially treatment of the disease, and enhance general understanding of the mechanisms of amyloidosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Physical map of the GDLD region.
Figure 2: Northern analysis of M1S1.
Figure 3: Electropherograms showing DNA sequences surrounding each of the four mutations (right) and segregation of the mutations as revealed by restriction endonuclease digestion and haplotype analysis.
Figure 4: Cellular localization of full-length and truncated M1S1.
Figure 5: Schematic representation of the structure of M1S1.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Nakaizumi, G. A rare case of corneal dystrophy. Acta Soc. Ophthalmol. Jpn 18, 949–950 (1914).

    Google Scholar 

  2. Mondino, B.J., Rabb, M.F., Sugar, J., Sundar Raj, C.V. & Brown, S.I. Primary familial amyloidosis of the cornea. Am. J. Ophthalmol. 92, 732–736 (1981).

    Article  CAS  Google Scholar 

  3. Weber, F.L. & Bable, J. Gelatinous drop-like dystrophy: a form of primary corneal amyloidosis. Arch. Ophthalmol. 98, 144–148 (1980).

    Article  CAS  Google Scholar 

  4. Smolin, G. Corneal dystrophies and degenerations. in Cornea (eds Smolin, G. & Thoft, R.) 499–533 (Little, Brown Company, Boston, 1994).

    Google Scholar 

  5. Santo, R.M., Yamaguchi, T., Kanai, A., Okisaka, S. & Nakajima, A. Clinical and histopathologic features of corneal dystrophies in Japan. Ophthalmology 102, 557–567 (1995).

    Article  CAS  Google Scholar 

  6. Tsujikawa, M. et al. Homozygosity mapping of a gene responsible for gelatinous drop-like corneal dystrophy (GDLD) to chromosome 1p. Am. J. Hum. Genet. 63, 1073–1077 (1998).

    Article  CAS  Google Scholar 

  7. Linnenbach, A.J. et al. Sequence investigation of the major gastrointestinal tumor-associated antigen gene family, GA733. Proc. Natl Acad. Sci. USA 86, 27–31 (1989).

    Article  CAS  Google Scholar 

  8. Miotti, S. et al. Characterization of human ovarian carcinoma-associated antigens defined by novel monoclonal antibodies with tumor-restricted specificity. Int. J. Cancer 39, 297–303(1987).

    Article  CAS  Google Scholar 

  9. Stein, R., Basu, A., Chen, S., Shih, L.B. & Goldenberg, D.M. Specificity and properties of MAb RS7-3G11 and the antigen defined by this pancarcinoma monoclonal antibody. Int. J. Cancer 55, 938–946 (1993).

    Article  CAS  Google Scholar 

  10. Malthiery, Y. & Lissitzky, S. Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complementary DNA. Eur. J. Biochem. 165, 491–498 (1987).

    Article  CAS  Google Scholar 

  11. Kiefer, M.C., Masiarz, F.R., Bauer, D.M. & Zapf, J. Identification and molecular cloning of two new 30-kDa insulin-like growth factor binding proteins isolated from adult human serum. J. Biol. Chem. 266, 9043–9049 (1991).

    CAS  PubMed  Google Scholar 

  12. El-Sewedy, T., Fornaro, M. & Alberti, S. Cloning of the murine TROP2 gene: conservation of a PIP2-binding sequence in the cytoplasmic domain of TROP2. Int. J. Cancer 75, 324–330 (1998).

    Article  CAS  Google Scholar 

  13. Yu, F.X., Sun, H.Q., Janmey, P.A. & Yin, H.L. Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. J. Biol. Chem. 267, 14616–14621 (1992).

    CAS  PubMed  Google Scholar 

  14. Pitcher, J.A. et al. Phosphatidylinositol 4,5-bisphosphate (PIP2)-enhanced G protein-coupled receptor kinase (GRK) activity. Location, structure, and regulation of the PIP2 binding site distinguishes the GRK subfamilies. J. Biol. Chem. 271, 249073–24913 (1996).

    Article  Google Scholar 

  15. Lambrechts, A. et al. The mammalian profilin isoforms display complementary affinities for PIP2 and proline-rich sequences. EMBO J. 16, 484–494 (1997).

    Article  CAS  Google Scholar 

  16. Basu, A., Goldenberg, D.M. & Stein, R. The epithelial/carcinoma antigen EGP-1, recognized by monoclonal antibody RS7-3G11, is phosphorylated on serine 303. Int. J. Cancer 62, 472–479 (1995).

    Article  CAS  Google Scholar 

  17. de la Chapelle, A., Kere, J., Sack, G.H., Tolvanen, R. & Maury, C.P. Familial amyloidosis, Finnish type: G654–a mutation of the gelsolin gene in Finnish families and an unrelated American family. Genomics 13, 898–901 (1992).

    Article  CAS  Google Scholar 

  18. Haltia, M. et al. Gelsolin gene mutation—at codon 187—in familial amyloidosis, Finnish: DNA-diagnostic assay. Am. J. Med. Genet. 42, 357–359 (1992).

    Article  CAS  Google Scholar 

  19. Munier, F.L. et al. Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nature Genet. 15, 247–251 (1997).

    Article  CAS  Google Scholar 

  20. Kawasaki, K. et al. One-megabase sequence analysis of the human immunoglobulin λ gene locus. Genome Res. 7, 250–261 (1997).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by a Research on Human Genome and Gene Therapy grant from Ministry of Health and Welfare of Japan.

Author information

Authors and Affiliations

  1. Division of Clinical Genetics, Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Japan

    Motokazu Tsujikawa, Hiroki Kurahashi & Yusuke Nakamura

  2. Department of Ophthalmology, Osaka University Medical School, Japan

    Motokazu Tsujikawa, Yoshikazu Shimomura & Yasuo Tano

  3. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan

    Toshihiro Tanaka & Yusuke Nakamura

  4. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Japan

    Kohji Nishida

Authors
  1. Motokazu Tsujikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroki Kurahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Toshihiro Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kohji Nishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshikazu Shimomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuo Tano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yusuke Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusuke Nakamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsujikawa, M., Kurahashi, H., Tanaka, T. et al. Identification of the gene responsible for gelatinous drop-like corneal dystrophy. Nat Genet 21, 420–423 (1999). https://doi.org/10.1038/7759

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/7759

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing